Nitric oxide (NO)has been reported to subserve many of the same mucosal protection mechanisms as prostaglandins and is sufficient for acute gastroprotection and ulcer healing. In fact, NO‐donating NSAID hybrid compounds such as the nitrooxybutyl ester of naproxen show reduced ulcerogenic activity while maintaining anti‐inflammatory activity. We introduce two prototypes of novel triple‐hybrid compounds consisting of cysteine which is known to enhance the activity of organic nitrates and to reduce nitrate tolerance, an NSAID (naproxen), and an organic nitrate (nitrooxypivaloic acid). L‐Cysteine ethyl ester first was N‐acylated in a CH2Cl2/H2O twophase system using the acid chlorides of naproxen or nitrooxypivaloic acid, respectively, and sodium acetate, or alternatively using the DCC‐activated nitrooxy acid in absolute CH2Cl2. The N‐acylated intermediates were subsequently S‐acylated using the acid chlorides or alternatively the carbonyldiimidazole (CDI)‐activated acids again. The two naproxen‐cysteine‐nitrate hybrid prodrugs were screened in vitro for their cyclooxygenase inhibitory properties relative to naproxen. In this screening the N‐nitrooxyacylcysteine derivative was found to be inactive in the concentration range of 0.1—10 μmol/L against both COX‐1 and COX‐2, while the S‐nitrooxyacylcysteine derivative had only weak activity against COX‐1.